1. Field of the Invention
This invention relates to novel derivatives of alkyl, phenyl or benzyl 16.beta.-methyl-3-oxoandrost-4-ene-17.beta.-thiocarboxylates and the corresponding androsta-1,4-dienes which are active anti-inflammatory agents in mammals. The invention further relates to pharmaceutically active compositions comprising a selected 17.beta.-thiocarboxylate of the invention in combination with a pharmaceutically acceptable excipient.
2. Prior Art
Certain 3-oxoandrost-4-ene 17.beta.-carboxylic acids which are substituted at the 9 position with chlorine or fluorine and at the 11 position with keto or hydroxy or chloro group are known. See for example U.S. Pat. Nos. 3,828,080 and 3,981,894 both to Phillipps et al. It is also known that 3-oxoandrost-4-ene 17.beta.-carboxylic acids or esters thereof may be substituted at the 6.alpha. position with fluoro and optionally at the 9.alpha. position with a fluoro. See for example U.S. Pat. Nos. 3,636,010 and 4,093,721 to Phillipps.
It is also known from U.S. Pat. No. 3,989,686 to Phillipps et al of Glaxo that steroids of the formula ##STR1## wherein R.sup.1 is H or CH.sub.3 ;
R.sup.2 is H or CH.sub.3 ; PA1 R.sup.3 is H or, when R.sup.2 is H, C.sub.1-6 alkoxy, C.sub.1-5 alkyl, thiocyanato or halogen; PA1 R.sup.4 is H or CH.sub.3 ; PA1 R.sup.5 is C.sub.1-6 alkyl optionally substituted by halo or NR.sup.6 R.sup.7, where R.sup.6 and R.sup.7 are the same or different C.sub.1-6 alkyl or R.sup.6 and R.sup.7 together with N are morpholino, thiamorpholine or morpholino substituted with C.sub.1-6 alkyl; and PA1 the dotted line in the "A" ring represents an optional double bond at these positions. These compounds are useful as anesthetics. PA1 X.sup.2 is hydrogen, fluoro, chloro or bromo; PA1 X.sup.3 is .dbd.C.dbd.O or ##STR3## or may also be ##STR4## when X.sup.2 is chloro; R is alkyl of 1 through 6 carbon atoms, or phenyl or benzyl optionally substituted with a substituent which is alkyl of 1 through 4 carbon atoms, alkoxy of 1 through 4 carbon atoms or halo; PA1 R.sup.1 is hydrogen or alkanoyl of 2 through 6 carbon atoms; and PA1 the bond between C-1 and C-2 is a double or single bond. PA1 X.sup.1 is hydrogen, fluoro, or chloro; PA1 X.sup.2 is hydrogen, fluoro, chloro or bromo; PA1 X.sup.3 is .dbd.C.dbd.O or ##STR5## or may also be ##STR6## when X.sup.2 is chloro; R is alkyl of 1 through 6 carbon atoms, or phenyl or benzyl optionally substituted with a substituent which is alkyl of 1 through 4 carbon atoms, alkoxy of 1 through 4 carbon atoms or halo; PA1 R.sup.1 is hydrogen or alkanoyl of 2 through 6 carbon atoms; and PA1 the bond between C-1 and C-2 is a double or single bond.
Methyl 3.beta.-acetoxyallothiolcholonate and methyl 3.beta.-acetoxy-etiothiochol-5-enate are also known. See, e.g., Jerger et al. Helv. Chem. Acta. 29, 684-92 (1947).
A heretofore unknown series of 16.beta.-methyl-3-oxo-androst-4-ene 17.beta.-thiocarboxylates and derivatives thereof has been discovered and is disclosed herein. The 17.beta.-thiocarboxylates exhibit topical anti-inflammatory activity and few adverse side effects.